Electrolytic reduction of cyclopentanophenanthrene derivatives



tats

Int. Cl. Billk 1/00 US. Cl. 204-72 6 Claims This invention relates to a novel process for the reduction of conjugated steroidal ketones by electrochemical means.

The expression conjugated steroidal ketone as used herein and in the appended claims is understood to refer to steroids having at least one ethylenically unsaturated carbon to carbon bond in conjugated relationship with at least one x0 or keto substituent.

Prior to the present invention, the conversion of conjugated steroidal ketones into desoxy steroids was accomplished chemically by reducing the 0x0 group by treatment with, for example, sodium borohydride, or the like, to the free alcohol followed by dehydration by treatment with a strong acid. Another method was to condense the oxo group with thiol or dithiol in the presence of zinc chloride or hydrochloric acid and dehydrating agent to form the thiol ketal which was then split off by treatment with Raney nickel or with an alkali metal in the presence of liquid ammonia. This and other prior art methods for the preparation of desoxy steroids are disadvantageous in that several conversion steps are necessary which are time consuming, expensive and difficult to operate. Further, the yield of desoxy steroid obtainable by prior art methods is relatively low.

A primary object of the present invention is to provide a process for the electrochemical reduction of a conjugated steroidal ketone into a conjugated desoxy polyene steroid which overcomes the aforementioned disadvantages. Another object of the present invention is to provide a process for the production of conjugated desoxy polyene steroids which is characterized by ease of operation and relatively high yields. Additional objects of the present invention will become apparent as the invention is hereinafter described in detail and from the appended claims.

In accordance with the present invention, the reduction of a conjugated steroidal ketone into the corresponding conjugated desoxy polyene steroid is accomplished by subjecting the steroidal ketone to electrochemical reduction at a cathode of low hydrogen overvoltage in an electrolytic medium comprising mineral acid electrolyte, water, and water miscible, inert organic solvent.

Conjugated steroidal ketones utilized as starting compounds in the novel process of this invention include steroids of the androstane, 19-norandostane, pregnane, 19-norpregnane, and cholestane series having an oxo substituent attached to a carbon atom of the steroid ring nucleus or to a carbon atom of a side chain. To illustrate the process of the present invention, the following diagrammatic illustrations are provided to exemplify the applicability of the process. For the sake of simplicity only, a partial formula of the steroid is shown. The steroid can optionally have other substituents present such as hydroxy, acyloxy, carboxylic acid, fluoro, bromo, chloro, amines, phenyl, alkyl, alkenyl, alkinyl, alkyl and cycloalkyl ethers, bismethylenedioxy, alkylenedioxy, and the like. An isolated or nonconjugated oxo substituent, if present, is reduced to the free alcohol which, if desired, can be regenerated by oxidation procedures known in the art as, for example, by treatment with chromium trioxide in pyridine, manganese dioxide, and the like. In the following partial formulas, R represents hydrogen or methyl.

Patented May 13, 1969 CH3 CH3 CH3 0 CH CH CH3 0 H3 CH3 (11) C H3 C H3 H3 (12) C H: C H3 0 H;

C (3H4 C H; 0 l-H 1H Q Q 15 Q (13) CH3 CH3 ll 0 H (14) C Ha C H: C H:

Conjugated steroidal ketones which may be employed in the process of the present invention as illustrated in the above partial formulas include the A -3-one steroids such as 2l-acetoxy-17a-hydroxypregn-1-ene-3, l 1,20-trione, cholest-l-en-B-one, 2-bromocholest-1-en-3-one, 2-bromocholest-l-ene-3,6-dione, 3-keto-l-bisnorallocholenic acid, 21-acetoxy-allopregn-l-ene-3,20-dione, l7B-hydroxyandrost-l-en-3-one, 1-methyl-17,8-hydroxyandrost-l-en-3-one, 1-methylandrost-1-ene-3,l7-dione, 9a-fluoro-11p,17p-dihydroxy-l7u-methylandr0st-Len- 3-one, 9a-fluoro-l7fi-hydroxy-17a-rnethylandrost-l-ene- 3,1 l-dione, cholest-1-ene-3,6-dione, and the like,

A -steroids such as Z-formylcholest-Z-ene, and the like,

A -3-one steroids such as Got-fluoro-19-nor-testoster0ne,

9a-fluoro-testosterone,

l9-hydroXy-testosterone,

cholest-4-ene-3,6-dione,

cholesta-4,6-dien-3-one,

progesterone,

19-nor-progesterone,

hydrocortisone,

corticosterone,

cortisone,

6a-fluoromethyl-l7u-hydroxypregn-4-ene-3,20-dione- 17-acetate,

6a-difiuoromethyl-17u-hydroxypregn-4-ene-3,20-dione- 17-acetate,

6a-trifluoromethylcortisone,

a-trilluoromethylcortisone,

6ot-trifluoromethyltestosterone,

6a-trifluorornethyl-l7ot-acetoxyprogesterone,

7B-hydroxycholest-4-en-3-one,

D-homotestosterone,

cholesta-4,7-dien-3-one,

2l-acetoxypregn-4-ene-3,l1,20-trione, and the like,

A -6-one steroids such as androst-4-ene-6, l7-dione, cholest-4-en-6-one, 3B-hydroxycholestl-en-6-one,

3 fl-acetoxycholest-4-en-6-one, 3fl-acetoxycholest-4-en-6-one, and the like,

A -keto steroids such as 17fl-hydroxyandrost-5-en-4-one, cholest-5-en-4-one, 3fl-acetoxyandrost-S-ene-Zl7-dione, 3,8,4,8-dihydroxycholest-5-ene-7-0ne, BB-acetoxy-l7B-hydroxyandrost-5-en-7-one, 318,l718-dihydr0xyandrost-5-en-7-one, 3B-acetoxycholest-5-en-7-one,

7 -keto-A -cholenic acid, and the like,

and other conjugated steroidal ketones such as 3B-hydroxy-cholest-8 (9) -en-7-0ne,

3 B-acetoxy-l4-hydroxycholest-8 (9 -ene-7, 15-dione, 3 3-hydroxy-5a-pregn-8 (9 -ene-7,20-dione,

3 3,1 1a,2OB-trihydroxy-Sa-pregn-S (9 -en-7-one, 3fi-acetoxycholest-8 14) -en-7-one, 3fi-acetoxycholest-8(14)-en-15-one,

3 fi-acetoxyandrost-fil 1 1 -ene-l2,17-dione, pregn-9 1 1 )-ene-3,12,20-trione,

pregn-l 6-ene-3,1 1,20-trione, SB-hydroxy-16-methylpregna-5,16-dien-20-one, BB-hydroxypregna-S,16-dien-20-one, and the like.

The conjugated desoxy steroids prepared by the novel process of the present invention are valuable intermediates for the preparation of pharmacological agents and also possess hormonal activity per se. By means of the present invention, l7B-hydroxyandrost-1-en-3-one, for example, is converted into androsta-l,3-diene-l7p-ol which possesses valuable anti-estrogenic, anti-gonadatrophic, anti-fibrillatory and appetite stimulating properties. Alternatively, androsta-1,3-diene-17fl-ol may be oxidized to the corresponding 17-keto derivative and then converted into 17,6-hydroxy-l7a-methyl, vinyl, or ethynyl derivatives thereof by methods known in the art which in addition to the foregoing properties are also useful as anabolic-androgenic agents with a favorable anabolicandrogenic ratio.

In practicing the process of the present invention, the conjugated steroidal ketone is introduced into the cathode compartment of an electrolysis cell. This is best accomplished by use of an organic solvent carrier which is water miscible and inert to the electrolytic action of the process. Suitable organic solvents for the present invention include ethers such as dioxane and tetrahydrofuran, lower monohydric alcohols such as methanol, ethanol, and isopropanol, polyhydric alcohols such as the lower alkylene glycols, e.g., ethylene glycol, propylene glycol, mixtures of the foregoing solvents, and the like. The amount of organic solvent in the system may vary considerably. The amount of organic solvent can range from that amount which is sufficient to dissolve or substantially dissolve the steroidal ketone up to about 94%, preferably about 20% to about 85% by weight of the electrolytic medium. The expression electrolytic medium as used herein includes the organic solvent, water and a mineral acid electrolyte.

The preferred electrolyte materials are sulfuric acid, hydrochloric acid, and perchloric acid; however, other mineral acids may also be employed such as hydrobromic acid, phosphoric acid, and the like. The amount of electrolyte present in the system is suitably within the range of about 0.5% to about 20% by weight of the electrolytic medium, preferably from about 1.0% to Due to the general instability of steroidal ketones in the presence of a high concentration of mineral acid, there is generally no advantage in employing an electrolyte concentration higher than The balance of the electrolytic medium consists essentially of water which is present in an amount at least sufficient to dissolve or provide good dispersion of the electrolyte and thereby render the electrolytic medium conductive to an electric current. The amount of water present should be at least 5% by weight of the electrolytic medium, preferably from about 10% to about 75%. A greater quantity of water may be employed depending upon such factors as the amount of organic solvent used, the solubility of the steroid employed, and the amount of electrolyte present.

The electrochemical reduction process of the present invention is conducted in an electrolytic cell having two compartments, an anode compartment and a cathode compartment, which are separated by a semipermeable membrane. The semipermeable membrane may be formed of any material which is inert to the electrolytic action and which permits passage of the ionic phase from one compartment to the other without permitting passage of the steroid material. Suitable membrane materials include clay, porous alumina, inert polymeric membranes such as polytetrafiuoroethylene, cellulose acetates, and the like.

Cathode materials which are used in the process of the present invention include the low hydrogen over-voltage materials such as copper, iron, graphite, aluminum, carbon, and silver, preferably a copper cathode such as copper or copper plate, i.e., a material such as brass or the like having a film of copper thereon. The cathode may be in any number of physical forms but preferably is in a form having the highest possible surface area for exposure to the electrolytic medium such as a sheet or a wire mesh grid. Advantageously, the cathode is sufficiently rigid to be used as a means for stirring or agitating the electrolytic medium. Alternatively, although not required, stirring or agitating means may be separately provided, as for example, a mechanical stirrer having agitating means formed of a material such as polytetrafluoroethylene, or the like which is inert to the electrolytic action.

The anode can be any difiiculty oxidizable conductor such as carbon, platinum, iron, lead, graphite and the like. In general, the anode material may be any conductor which is not attacked by the electrolytic medium in a manner which would readily transform the anode material into a soluble state.

The process of the present invention can be conducted at a temperature within the range of about 0 C. to about 60 C., preferably from about 10 C. to about 40 C. Higher temperatures may be used but, in general, there is no advantage in doing so in that an increase in temperature generally causes a decrease in the yield of the final product. The most beneficial temperature for the reduction of a particular conjugated steroidal ketone is readily determinable by one of ordinary skill giving due consideration to such factors as the amount of electrolyte, the current, the concentration of steroid, the cathode material, and the like.

In electrochemically reducing a conjugated steroidal ketone into the corresponding conjugated desoxy polyene by the process of this invention, a current density within the range of about 0.01 to about 0.5 ampere per square centimeter is used, preferably from about 0.05 to about 0.5 ampere/cm. Depending primarily upon the current density and the current efiiciency, a reaction time of the order of about 0.5 toabout 10 hours is sufficient. The most beneficial reaction time for the reduction of a particular steroidal ketone is readily determinable by one of ordinary skill in the art giving due consideration to such factors as the current density, current efficiency, concentration of steroid, cathode material, temperature, and the like. As a rule, a current within the above range is applied for a time sufficient to pass the equivalent of at least two Faradays per mole of steroidal ketone of electric current at the current employed. However, in view of the fact that an electrolysis system normally operates at a current efficiency of from forty to eighty percent, a greater amount of electricity is employed. Thus, for a system operating at about fifty percent efiiciency, the equivalent of at least four Faradays, perfera'bly in slight excess thereof, per mole of steroid is employed. In the case of conjugated steroidal ketones containing more than one oxo substituent, a greater amount of electricity is required.

In practicing the process of the present invention, the concentration of conjugated steroidal ketone in the cathode compartment may vary considerably. Desirably, the concentration of steroid is maintained at a maximum to achieve the greatest efiiciency for transformation of the conjuiated steroidal ketone into the desoxy steroid. In general, a concentration of steroid within the range of about 0.1 to about 20% by weight of the electrolytic medium, preferably from about 1% to about 15%, is employed. Higher concentrations may be used, if desired. For example, a suspension of steroid may be used in which case the reduction product, i.e., the desoxy polyene steroid, should be soluble in the organic phase of the reaction mixture.

An electrolysis cell suitable for practicing the process of the present invention consists of a rectangular block of Plexiglas having an anode compartment in communication with a cathode compartment of equal volume. The passage between the two compartments is provided with a semi-permeable membrane, e.g., a cellulose dialysis membrane, which permits free passage of the ionic phase but yet restricts movement of the steroidal material to the cathode compartment. A suitable cellulose dialysis membrane is a regenerated cellulose prepared by the viscose process and which has a pore radius of 24 angstroms as determined by the average rate of water flow through a film of the material. Other two compartment electrolysis cells can be used to practice the process of the present invention, the foregoing only being illustrative.

The following examples serve to illustrate but are not intended to limit the scope of the present invention.

EXAMPLE 1 Into the cathode compartment of an electrolysis cell provided with a lead anode and a copper plated brass sheet cathode, each electrode measuring about 1 cm. x 3 cm. x 1.6 mm., there is added 0.2 g. of 17,8-hydroxyandrost-4-en-3-one in 50 ml. of dioxane. Thereafter, a mixture of 50 ml. of water and 2.5 ml. of concentrated sulfuric acid is added to the cathode compartment. A current of 0.1 amps/cm? is then applied for about 2 hours while stirring the reaction mixture in the cathode compartment. Thereafter the current is shut off and the reaction solution is removed from the cell. The reaction mixture is then concentrated under vacuum and the thus-obtained residue diluted with water. The resulting mixture is then extracted with chloroform and the organic phase is separated, washed, dried and concentrated to dryness to yield androsta-3,-dien-175-01.

EXAMPLE 2 By repeating the procedure of Example 1 using as the starting material the conjugated steroidal ketones listed under Column I, the corresponding conjugated desoxy polyene steriods appearing under Column II are obtained.

I II

l-methylandrost-l-en-3,17-dione. l-methylandrosta-l,3dien-171S-ol. 9rz-finoroandrost-4-en-3,17-dione. 9a-fiuoroandrosta-ELS-diene-l7 3-01. 17B-hydroxyandrosta-1,4-dien-3-one Androsta-Lfl,5-triene47B-ol. 17fl-hydroxyandrosta-4,6-diene-3- Androsta-3,5 ,7-triene-17fl-ol and one. androsta-2,4,6-triene-l7B-ol.

6a4;uoro-l7a-vinylestra-3,5-diene- 1 8- 17 3-hydroxyandrost-1-en-3-one Androsta-l,3-dien-17B0l.

EXAMPLE 4 To a mixture of 2 grams of progesterone in about 65 ml. of ethanol in the cathode compartment of an electrolysis cell provided with a copper cathode and a carbon anode, each electrode having an area of about 3 em. there is introduced 40 ml. of water and 5 ml. of concentrated sulfuric acid. A current density of 0.09 ampere per sq. centimeter is applied for about 4.5 hours while slowly stirring the electrolytic medium in the cathode compartment. Thereafter, the mixture is removed from the cell, concentrated under vacuum and the residue diluted with water. The resulting mixture is then extracted with chloroform and the organic phase is separated, washed, dried and concentrated to dryness to yield pregna-3,5-dien- 205-01.

EXAMPLE 5 By repeating the procedure of Example 1, the con jugated ketones listed under Column I are converted into the corresponding conjugated desoxy polyene steroids listed under Column II.

I II

What is claimed is:

1. A process for the reduction of a conjugated steroidal ke-tone into a conjugated desoxy polyene steroid which comprises subjecting a conjugated steroid-a1 ketone to electrochemical reduction at a cathode of low hydrogen overvolt-age in an electrolytic medium comprising mineral acid electrolyte, water and water miscible, inert organic solvent.

2. A process according to claim 1 wherein said cathode is selected from the group consisting of copper, iron, graphite, aluminum, carbon and silver.

3. A process according to claim 1 wherein said cathode is selected from the group consisting of copper, iron, graphite, aluminum, carbon and silver and said mineral acid electrolyte is selected from the group consisting of sulfuric acid, hydrochloric acid, and perchloric acid.

4. A process according to claim 1 wherein said electrochemical reduction is conducted at a cathode selected from the group consisting of copper, iron, graphite, aluminum, carbon and silver in an electrochemical medium comprising mineral acid electrolyte, Water and water miscible, inert organic solvent at a current density within the range of about 0.01 to about 0.5 ampere per cm. said mineral acid being selected from the group consisting of sulfuric acid, hydrochloric acid, and perchloric acid.

5. A process according to claim 4 wherein said current density is within the range of 0.05 to 0.5 ampere per cm.

6. A process according to claim 1 wherein said cathode is copper, said mineral acid electrolyte is selected from the group consisting of sulfuric acid, hydrochloric acid, and perchloric acid, and said reduction is accomplished at a current density of 0.05 to 0.5 ampere per cm.

HOWARD S. WILLIAMS, Primary Examiner.

M. FLOURNOY, Assistant Examiner.

US. Cl. X.R. 

1. A PROCESS FOR THE REDUCTION OF A CONJUGATED STEROIDAL KETONE INTO A CONJUGATED DESTOXY POLYENE STEROID WHICH COMPRISES SUBJECTING A CONJUGATED STEROIDAL KETONE TO ELECTGROCHEMICAL REDUCTION AT A CATHODE OF LOW HYDROGEN OVERVOLTATE IN AN ELECTROLYTIC MEDIUM COMPRISING MINERAL ACID ELECTROLYTE, WATER AND WATER MISCIBLE, INERT ORGANIC SOLVENT. 